1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Sci Rep. 2014 May 2;4:4874. doi: 10.1038/srep04874.
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.
c-Abl 在帕金森病（PD）患者的大脑和 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒的小鼠中被激活，通过酪氨酸磷酸化抑制 parkin，导致 parkin 底物的积累和神经元细胞死亡。在本研究中，我们评估了 nilotinib（一种脑穿透 c-Abl 抑制剂）在急性 MPTP 诱导的 PD 模型中的体内疗效。我们的结果表明，nilotinib 的给药可降低 c-Abl 的激活和 parkin 底物 PARIS 的水平，从而防止 MPTP 中毒后多巴胺（DA）神经元的丢失和行为缺陷。另一方面，我们观察到 parkin 和 parkin 底物 AIMP2 的酪氨酸磷酸化没有减少，这表明 nilotinib 的保护作用可能部分是 parkin 非依赖性的，或者是 nilotinib 的药效学特性所致。这项研究为测试其他脑穿透 c-Abl 抑制剂作为治疗 PD 的潜在治疗药物提供了强有力的依据。
